2020
DOI: 10.1016/j.redox.2020.101656
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Dynamic regulation of NADPH oxidase 5 by intracellular heme levels and cellular chaperones

Abstract: NADPH oxidase 5 (NOX5) is a transmembrane signaling enzyme that produces superoxide in response to elevated cytosolic calcium. In addition to its association with numerous human diseases, NOX5 has recently been discovered to play crucial roles in the immune response and cardiovascular system. Details of NOX5 maturation, and specifically its response to changes in intracellular heme levels have remained unclear. Here we establish an experimental system in mammalian cells that allows us to probe the influence of… Show more

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Cited by 14 publications
(11 citation statements)
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“…Heme can act in a similar manner. For example, hsp90-driven heme incorporation into monomeric NOS subunits drives their conversion into functional homodimers ( 18 , 42 44 ), and heme binding within NADPH oxidase 5 promotes its active oligomer formation in cell membranes ( 45 ). Heme binding also causes protein partner exchange for a gain in function, as shown here and previously for sGC ( 32 ) and also for myoglobin ( 46 ), hemoglobin β and γ ( 47 ), BACH1 ( 48 ), and REV-ERBβ ( 49 ).…”
Section: Discussionmentioning
confidence: 99%
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“…Heme can act in a similar manner. For example, hsp90-driven heme incorporation into monomeric NOS subunits drives their conversion into functional homodimers ( 18 , 42 44 ), and heme binding within NADPH oxidase 5 promotes its active oligomer formation in cell membranes ( 45 ). Heme binding also causes protein partner exchange for a gain in function, as shown here and previously for sGC ( 32 ) and also for myoglobin ( 46 ), hemoglobin β and γ ( 47 ), BACH1 ( 48 ), and REV-ERBβ ( 49 ).…”
Section: Discussionmentioning
confidence: 99%
“…Likewise, we found that hsp90, which must bind with apo-sGCβ in cells to enable its heme insertion during maturation ( 17 19 ), was also needed for the NO-driven process. This implies that NO acts on the same machinery that cells employ to deliver and insert heme during normal sGC maturation ( 19 , 20 ), and for normal maturation of NOS enzymes ( 45 ) and globins ( 56 ). Whether NO acts through a common mechanism to reallocate heme to these or other hemeproteins is an exciting possibility that can now be explored.…”
Section: Discussionmentioning
confidence: 99%
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“…Hsp90 has been shown to bind to the C-terminal domain of NOX5 and regulate its superoxide production, suggesting that Hsp90 may regulate certain parameters of cellular redox [55]. More recently, a study identified a more dynamic regulatory control over NOX5 activity by modulating its heme via intracellular heme levels and Hsp90 [58], however, such studies require physiological semblances and follow up studies are needed.…”
Section: Role Of Hsp90 In Client Hemeprotein Maturationmentioning
confidence: 99%
“…In addition to these widely known roles for heme in biology, there is now a substantial body of evidence that identifies heme as a regulator of various cellular activities. The first report, to our knowledge, of heme as a regulator was as far back as 1975, when heme was observed as regulating the synthesis of δ-aminolevulinic acid synthase which catalyzes the first step of the 8-step heme biosynthesis pathway . We see chemical logic in the concept of regulatory mechanisms in cells that are linked to heme binding, but the idea of heme as a regulator laid dormant in the literature for many years.…”
Section: Introductionmentioning
confidence: 99%